tbuckley/cabot-search huggingface dataset:
Inactivated whole-virion SARS-CoV-2 vaccines and long-term clinical outcomes in patients with coronary atherosclerosis disease in China: a prospective cohort study
Authors: Huajie Xu, Jiaojiao Zheng, Xin Zhao, Qi Zhou, Bing Fan, Hongyi Wu, Si Zhang, Junbo Ge
Journal: Cardiovascular Research (2023)

Publicized adverse events after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) raised concern among patients with coronary atherosclerosis disease (CAD). We sought to study the association between SARS-CoV-2 vaccines and long-term clinical outcomes including ischaemic and bleeding events among patients with CAD.Inpatients diagnosed with CAD by coronary angiography, without a history of SARS-CoV-2 infection and vaccination, were included between 1 January and 30 April 2021, and underwent follow-up until 31 January 2022. Two doses of inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, BBIBPCorV, or WIBP-CorV) were available after discharge, and the group was stratified by vaccination. The primary composite outcomes were cardiovascular death, non-fatal myocardial infarction, stent thrombosis, unplanned revascularization, ischaemic stroke, venous thrombo-embolism, or peripheral arterial thrombosis. The bleeding outcomes were Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding. Cox regression models with vaccination status as a time-dependent covariate were used to calculate the hazard ratio (HR) for the outcomes. A propensity score matching method was used to reduce confounding biases. This prospective cohort study included 2078 individuals with CAD, 1021 (49.1%) were vaccinated. During a median follow-up of 9.1 months, 45 (4.3%) primary composite outcomes occurred in the unvaccinated group, and 33 (3.2%) in the vaccinated group. In Cox regression, the adjusted HR was 1.13 [95% confidence interval (CI) 0.65-1.93]. The adjusted HR for the bleeding outcomes associated with vaccination was 0.81 [95% CI 0.35-1.19]. After matching, the adjusted HR for the primary composite outcomes associated with vaccination was 1.06 [95% CI 0.57-1.99] and for the bleeding outcomes was 0.91 [95% CI 0.35-2.38]. Similar results were found in the seven prespecified subgroups. No grade 3 adverse reactions after vaccination were recorded.Our results indicated no evidence of an increased ischaemic or bleeding risk after vaccination with inactivated SARS-CoV-2 vaccine among Chinese patients with CAD, with limited statistical power.
Modeling brain and neural crest neoplasms with human pluripotent stem cells
Authors: Cedar Schloo, Lena M Kutscher
Journal: Neuro-Oncology (2023)

Abstract Pluripotent stem cells offer unique avenues to study human-specific aspects of disease and are a highly versatile tool in cancer research. Oncogenic processes and developmental programs often share overlapping transcriptomic and epigenetic signatures, which can be reactivated in induced pluripotent stem cells. With the emergence of brain organoids, the ability to recapitulate brain development and structure has vastly improved, making in vitro models more realistic and hence more suitable for biomedical modeling. This review highlights recent research and current challenges in human pluripotent stem cell modeling of brain and neural crest neoplasms, and concludes with a call for more rigorous quality control and for the development of models for rare tumor subtypes.
Serum biomarker-based endotypes of atopic dermatitis in China and prediction for efficacy of dupilumab
Authors: Yuemeng Wu, Chaoying Gu, Shangshang Wang, Huibin Yin, Zhuoqiong Qiu, Yang Luo, Zheng Li, Ce Wang, Xu Yao, Wei Li
Journal: British Journal of Dermatology (2023)

Abstract Background Atopic dermatitis (AD) is a highly heterogeneous disease clinically and biologically. Serum biomarkers have been utilized for endotype identification and have the potential to be predictors for treatment. Objectives To explore the serum biomarker-based endotypes of Chinese patients with AD and to identify biomarkers for prediction of the efficacy of dupilumab. Methods Sera from 125 patients with moderate-to-severe AD and 60 normal controls (NC) were analysed for 24 cytokines/chemokines using the magnetic Luminex assay. After the patients received 16 weeks of dupilumab treatment, the efficacy was evaluated, and blood eosinophils, serum immunoglobulin (Ig) E and biomarkers were measured. Results Chinese patients with moderate-to-severe AD were characterized by T-helper (Th)2-dominant serum biomarkers that were mixed with differentially increased Th1-, Th17- and Th22-type cytokines/chemokines, and it was mainly Th2-type serum biomarkers that were positively correlated with disease severity and eosinophil counts. Adult (but not adolescent or elderly) patients with AD showed a consistent and more significant increase of biomarkers across different types of inflammation. The patients were grouped into two clusters by unsupervised k-means analysis, which were differentially associated with inflammation. Treatment with dupilumab decreased the levels of most cytokines/chemokines analysed. While there was no difference between the two clusters in the efficacy of dupilumab, baseline levels of CD25/soluble interleukin (sIL)-2Rα, IL-31 and IL-36β were identified as predictive factors associated with the efficacy. Conclusions Our study revealed two inflammation-related endotypes of Chinese patients with AD based on serum biomarkers. High levels of CD25/sIL-2Rα, IL-31 and IL-36β might predict good efficacy of dupilumab treatment.
BAM15 treats mouse sepsis and kidney injury, linking mortality, mitochondrial DNA, tubule damage, and neutrophils
Authors: Naoko Tsuji, Takayuki Tsuji, Tetsushi Yamashita, Naoki Hayase, Xuzhen Hu, Peter S.T. Yuen, Robert A. Star
Journal: Journal of Clinical Investigation (2023)

Sepsis pathogenesis is complex and heterogeneous; hence, a precision-medicine strategy is needed. Acute kidney injury (AKI) following sepsis portends higher mortality. Overproduction of mitochondrial ROS (mtROS) is a potential mediator of sepsis and sepsis-induced AKI. BAM15, a chemical uncoupler, dissipates mitochondrial proton gradients without generating mtROS. We injected BAM15 into mice at 0, 6, or 12 hours after cecal ligation and puncture (CLP), and these mice were treated with fluids and antibiotics. BAM15 reduced mortality, even after 12 hours, when mice were ill, and BAM15 reduced kidney damage and splenic apoptosis. Serial plasma and urinary mitochondrial DNA (mtDNA) levels increased after CLP and decreased after BAM15 administration (at 0 or 6 hours). In vitro septic serum proportionately increased mtROS overproduction and mtDNA release from kidney tubule cells, which BAM15 prevented. BAM15 decreased neutrophil apoptosis and mtDNA release; neutrophil depletion counteracted BAM15 benefits. Further, mtDNA injection in vivo replicated inflammation and kidney injury, which was prevented by BAM15. A large dose of exogenous mtDNA reversed protection by BAM15. We conclude that BAM15 is an effective preventive and therapeutic candidate in experimental sepsis and that BAM15 and mtDNA, a potential drug-companion diagnostic/drug-efficacy pair for clinical sepsis, are mechanistically linked via mtROS.
Association Between Antimicrobial Stewardship Programs and Antibiotic Use Globally
Authors: Kyaw Zay Ya, Phyo Thet Naing Win, Julia Bielicki, Mark Lambiris, Günther Fink
Journal: JAMA Network Open (2023)

Importance Antimicrobial resistance continues to spread rapidly at a global scale. Little evidence exists on the association of antimicrobial stewardship programs (ASPs) with the consumption of antibiotics across health care and income settings. Objective To synthesize current evidence regarding the association between antimicrobial stewardship programs and the consumption of antibiotics globally. Data Sources PubMed, Web of Science, and Scopus databases were searched from August 1, 2010, to Aug 1, 2020. Additional studies from the bibliography sections of previous systematic reviews were included. Study Selection Original studies of the association of ASPs with antimicrobial consumption across health care and income settings. Animal and environmental studies were excluded. Data Extraction and Synthesis Following the Preferred Reporting Items in Systematic Reviews and Meta-Analyses guideline, the pooled association of targeted ASPs with antimicrobial consumption was measured using multilevel random-effects models. The Effective Public Health Practice Project quality assessment tool was used to assess study quality. Main Outcomes and Measures The main outcome measures were proportion of patients receiving an antibiotic prescription and defined daily doses per 100 patient-days. Results Overall, 52 studies (with 1 794 889 participants) measured the association between ASPs and antimicrobial consumption and were included, with 40 studies conducted in high-income countries and 12 in low- and middle-income countries (LMICs). ASPs were associated with a 10% (95% CI, 4%-15%) reduction in antibiotic prescriptions and a 28% reduction in antibiotic consumption (rate ratio, 0.72; 95% CI, 0.56-0.92). ASPs were also associated with a 21% (95% CI, 5%-36%) reduction in antibiotic consumption in pediatric hospitals and a 28% reduction in World Health Organization watch groups antibiotics (rate ratio, 0.72; 95% CI, 0.56-0.92). Conclusions and Relevance In this systematic review and meta-analysis, ASPs appeared to be effective in reducing antibiotic consumption in both hospital and nonhospital settings. Impact assessment of ASPs in resource-limited settings remains scarce; further research is needed on how to best achieve reductions in antibiotic use in LMICs.
Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP
Authors: Yuxi Sun, Mengqiu Ma, Dandan Cao, Ancheng Zheng, Yiying Zhang, Yang Su, Jianfang Wang, Yanhua Xu, Mi Zhou, Yansong Tang, Yifan Liu, Teng Ma, Aoyuan Fan, Xiaoying Zhang, Qiaoling Zhu, Jiachen Qin, Chunyang Mo, Yawei Xu, Li Zhang, Dachun Xu, Rui Yue
Journal: Circulation Research (2023)

Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI.Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis.We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap.This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.
O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission
Authors: Jun Fan, Fang Guo, Ran Mo, Liang-Yu Chen, Jia-Wen Mo, Cheng-Lin Lu, Jing Ren, Qiu-Ling Zhong, Xiao-Jing Kuang, You-Lu Wen, Ting-Ting Gu, Jin-Ming Liu, Shu-Ji Li, Ying-Ying Fang, Cunyou Zhao, Tian-Ming Gao, Xiong Cao
Journal: Journal of Clinical Investigation (2023)

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.
Efficient detection and monitoring of pediatric brain malignancies with liquid biopsy based on patient-specific somatic mutation screening
Authors: Marija Kojic, Mellissa K Maybury, Nicola Waddell, Lambros T Koufariotis, Venkateswar Addala, Amanda Millar, Scott Wood, John V Pearson, Jordan R Hansford, Tim Hassall, Brandon J Wainwright
Journal: Neuro-Oncology (2023)

Abstract Background Brain cancer is the leading cause of cancer-related death in children. Early detection and serial monitoring are essential for better therapeutic outcomes. Liquid biopsy has recently emerged as a promising approach for detecting these tumors by screening body fluids for the presence of circulating tumor DNA (ctDNA). Here we tested the limits of liquid biopsy using patient-specific somatic mutations to detect and monitor primary and metastatic pediatric brain cancer. Methods Somatic mutations were identified in 3 ependymoma, 1 embryonal tumor with multilayered rosettes, 1 central nervous system neuroblastoma, and 7 medulloblastoma patients. The mutations were used as liquid biomarkers for serial assessment of cerebrospinal fluid (CSF) samples using a droplet digital PCR (ddPCR) system. The findings were correlated to the imaging data and clinical assessment to evaluate the utility of the approach for clinical translation. Results We developed personalized somatic mutation ddPCR assays which we show are highly specific, sensitive, and efficient in detection and monitoring of ctDNA, with a positive correlation between presence of ctDNA, disease course, and clinical outcomes in the majority of patients. Conclusions We demonstrate the feasibility and clinical utility of personalized mutation-based liquid biopsy for the surveillance of brain cancer in children. However, even with this specific and sensitive approach, we identified some potential false negative analyses. Overall, our results indicate that changes in ctDNA profiles over time demonstrate the great potential of our specific approach for predicting tumor progression, burden, and response to treatment.
Complement‐targeted therapeutics: An emerging field enabled by academic drug discovery
Authors: Christina Lamers, Daniel Ricklin, John D. Lambris
Journal: American Journal of Hematology (2023)

Abstract Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late‐stage clinical trials has expanded remarkably. The sudden emergence of this target area in the pipelines of many biotech start‐ups and even large pharmaceutical companies appears even more surprising when considering that the involvement of the complement system in various clinical conditions had long been recognized. In many aspects, however, the complement system is far from being a traditional drug target, which may explain the delayed breakthrough of this therapeutic strategy. While complement modulation is now considered an attractive “platform technology” with applications in a wide spectrum of disorders, the broad yet heterogeneous disease involvement of the complement system has long restricted its placement in traditional drug discovery programs. Concerns about the safety of complement‐targeted interventions, the large number and high plasma concentrations of target proteins, and the complexity of the complement system's engagement in biological processes are among other factors that kept complement off the drug discovery radar for decades. Alongside technical advances and financial incentives, the innovation and persistence of academic and clinical researchers have been the critical driving force to navigate complement therapeutics out of the shadow into the spotlight. In this commentary, we document this remarkable development using select examples and aim to venture some predictions where this promising field may be headed to.
The MaxCombo Test Severely Violates the Type I Error Rate—Reply
Authors: Pralay Mukhopadhyay, Satrajit Roychoudhury, Keaven M. Anderson
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Assessment of Phase 3 Randomized Clinical Trials Including Patients With Leptomeningeal Disease
Authors: Alisha E. Sharma, Kathryn Corbett, Hany Soliman, Arjun Sahgal, Sunit Das, Mary Jane Lim-Fat, Katarzyna J. Jerzak
Journal: JAMA Oncology (2023)

This systematic review examines the proportion of patients with leptomeningeal disease included in phase 3 randomized clinical trials for patients with metastatic breast cancer, lung cancer, and melanoma.
Mpox—A Rapidly Evolving Disease
Authors: Edward W. Cowen, Eric R. Tkaczyk, Scott A. Norton, Kieron S. Leslie
Journal: JAMA Dermatology (2023)

The 2022 mpox outbreak has rapidly emerged onto the global medical scene while the world continues to grapple with the COVID-19 pandemic. Unlike COVID-19, however, most patients with mpox present with skin findings, the evolving clinical presentation of which may be mistaken for other common skin diseases, particularly sexually transmitted infections. This Special Communication provides an overview of the evolution of mpox skin findings from its initial description in humans in 1970 to the present-day multinational outbreak.
PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages
Authors: Winson S. Ho, Isha Mondal, Beisi Xu, Oishika Das, Raymond Sun, Pochin Chiou, Xiaomin Cai, Foozhan Tahmasebinia, Elizabeth McFadden, Caren Yu-Ju Wu, Zhihao Wu, William Matsui, Michael Lim, Zhipeng Meng, Rongze Olivia Lu
Journal: Journal of Clinical Investigation (2023)

Stimulator of IFN genes type I (STING-Type I) IFN signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonists as monotherapy have shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in macrophages. Mice with macrophage PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human patients with glioblastoma (GBM), YAP/TAZ was highly expressed in tumor-associated macrophages but not in nontumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor-conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in tumor-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.
The MaxCombo Test Severely Violates the Type I Error Rate
Authors: Dominic Magirr, Carl-Fredrik Burman
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal